Basic and Translational Science
This theme benefits from existing expertise in basic science focusing on cell biology, vascular pathophysiology and neuroinflammation. Areas of interest include the maternal influence on fetal cerebrovascular development, the effects of diabetes and anti-diabetic drugs on models of tauopathy and the toxicity of different tau species to aid a molecular level understanding of dementia biology. The theme has expertise in neuronal and glial biology, cerebrovascular drainage pathways and the role of neuroinflammation in neurodegeneration, brain ageing and dementia.
The theme already works across disciplines, including mathematics, computer science, clinical services (neurosurgery, neurology, cardiothoracic surgery and anaesthetics) and the pharmaceutical industry, making use of biofilm, millifluidics, mass spectrometry and imaging facilities available in Southampton. There are many established national and international collaborations in place. The theme is well represented at international meetings with many emerging insights in the field related to immunological and vascular mechanisms emerging from work in Southampton.
Dr Tracey Newman is Associate Professor in Clinical Neurosciences within Medicine at the University of Southampton. She leads a multidisciplinary group that investigates immune mediated mechanisms that lead to neuronal injury, and its consequences, in the central nervous system. Members of the group are developing the use of biocompatible nanoparticle delivery and reporter systems.
Roxana Carare is a medically qualified Professor of Clinical Neuroanatomy and experimental neuropathology in the University of Southampton. Having graduated in general medicine in 1994 in Bucharest, Roxana completed her PhD in experimental neuropathology in 2006, in the University of Southampton, UK. The main international recognition for Roxana Carare has come from the neuroanatomy and neuropathology interdisciplinary research she leads, demonstrating the unique lymphatic drainage pathways by which fluid and soluble amyloid are eliminated from the brain along basement membranes within the walls of cerebral capillaries and arteries (Intramural Periarterial Drainage Pathways, IPAD).
Jessica Teeling is a professor in Experimental Neuroimmunology within Biological Sciences at the University of Southampton. Her research focuses on understanding the immune regulatory pathways in the healthy, diseased and ageing central nervous system (CNS). Her group studies the effect of antibody mediated inflammation in the CNS, and how these responses may contribute to the pathogenesis of neuroinflammatory and neurodegenerative diseases, such as Alzheimer’s disease, age related macular degeneration and systemic lupus erythematosis. She is particularly interested in the role of Fcgamma receptors and microglial activation.
Dr Amritpal Mudher is a Associate Professor in Neurosciences within Biological Sciences at the University of Southampton. The overarching aim of her research is to investigate the mechanisms that underpin tau-mediated dysfunction and degeneration in tauopathies such as Alzheimer’s disease and fronto-temporal dementia (see Mudher et al 2004, Mol Psychiatry, Chee et al 2005 for early investigations). This work led her team to identify disease-modifying tau-centred therapeutic targets (See Quriase et al 2013 Mol. Psychiatry). It has also raised interesting questions about the pathological significance of established tau aggregates such as soluble forms of tau, tau oligomers and tau filaments. More recently she is assessing whether tau-mediated axonal degeneration is wallerian in nature.
Sumeet Mahajan is a Professor in Molecular Biophotonics & Imaging in Chemistry with a joint appointment in the Institute for Life Sciences at the University of Southampton. His group works at the life science interface. The overarching aim of the research in his group is to develop new spectroscopy and imaging techniques and apply them to extract chemical information from biological systems to understand disease processes for early, faster or more sensitive healthcare diagnostics.
Computational modelling shows that innervation of vascular smooth muscle cells provides the motive force for IPAD, which has led us to hypothesize that 1) failure of elimination of Aβ along IPAD pathways could be a major factor in the pathogenesis of AD and 2) LC deafferentation of vascular smooth muscle cells (VSMCs) promotes IPAD failure in AD by impairing the motive force driving this clearance pathway.
Our lab is focused to studying the population of microglial cells from development to ageing, as well as chronic neurodegenerative disease such as Alzheimer’s. We have ongoing projects studying both rodent and human microglia, characterising it’s dynamics and phenotype with a range of techniques such as molecular phenotyping, scRNAseq, as well as modulating their activity via pharmacological or transgenic interventions. We are particularly interested in the role of proliferation and senescence in the specification of detrimental microglial phenotypes that can be targeted as a therapeutic approach in Dementia.
An association exists between intracranial pulsing and cognitive decline. This is seen in blood and CSF flow. Increased arterial stiffness is a possible mechanism; measures of pressure pulsing would help to confirm this. While flow measurements can be made relatively easily, intracranial pressure measurements are challenging. We have developed a novel approach measuring pulsations of the tympanic membrane and shown this to be associated with the MOCA cognitive assessment test in healthy subjects. There would be good support for a clinical academic trainee to explore these measurements of CSF dynamics in cognitively impaired patients.
Alzheimer’s disease (AD), Lewy Body Dementia (DLB) and Parkinson’s Disease (PD) have complex aetiology and pathogenesis and predicting the rate of clinical progression remains challenging. In Southampton, we showed that systemic inflammation increases the risk for earlier onset and/or progression of AD. In this project we will perform an in-depth analysis of serum and CSF samples to link pathways of inflammation to clinical progression. We will also measure amyloid, tau and alpha-synuclein and use state-of-the-art biophysical technology to link inflammation to specific conformers Collectively, this work may lead to novel composite biomarker to allow better diagnosis and allow better prediction of cognitive decline.